People may advise you to listen to your gut instincts: now research suggests that your gut may have more impact on your thoughts than you ever realized. Scientists from the Karolinska Institute in Sweden and the Genome Institute of Singapore led by Sven Pettersson recently reported in the Proceedings of the National Academy of Sciences that normal gut flora, the bacteria that inhabit our intestines, have a significant impact on brain development and subsequent adult behavior.

We human beings may think of ourselves as a highly evolved species of conscious individuals, but we are all far less human than most of us appreciate. Scientists have long recognized that the bacterial cells inhabiting our skin and gut outnumber human cells by ten-to-one. Indeed, Princeton University scientist Bonnie Bassler compared the approximately 30,000 human genes found in the average human to the more than 3 million bacterial genes inhabiting us, concluding that we are at most one percent human. We are only beginning to understand the sort of impact our bacterial passengers have on our daily lives.

Moreover, these bacteria have been implicated in the development of neurological and behavioral disorders. For example, gut bacteria may have an influence on the body’s use of vitamin B6, which in turn has profound effects on the health of nerve and muscle cells. They modulate immune tolerance and, because of this, they may have an influence on autoimmune diseases, such as multiple sclerosis. They have been shown to influence anxiety-related behavior, although there is controversy regarding whether gut bacteria exacerbate or ameliorate stress related anxiety responses. In autism and other pervasive developmental disorders, there are reports that the specific bacterial species present in the gut are altered and that gastrointestinal problems exacerbate behavioral symptoms. A newly developed biochemical test for autism is based, in part, upon the end products of bacterial metabolism.

But this new study is the first to extensively evaluate the influence of gut bacteria on the biochemistry and development of the brain. The scientists raised mice lacking normal gut microflora, then compared their behavior, brain chemistry and brain development to mice having normal gut bacteria. The microbe-free animals were more active and, in specific behavioral tests, were less anxious than microbe-colonized mice. In one test of anxiety, animals were given the choice of staying in the relative safety of a dark box, or of venturing into a lighted box. Bacteria-free animals spent significantly more time in the light box than their bacterially colonized littermates. Similarly, in another test of anxiety, animals were given the choice of venturing out on an elevated and unprotected bar to explore their environment, or remain in the relative safety of a similar bar protected by enclosing walls. Once again, the microbe-free animals proved themselves bolder than their colonized kin.

Pettersson’s team next asked whether the influence of gut microbes on the brain was reversible and, since the gut is colonized by microbes soon after birth, whether there was evidence that gut microbes influenced the development of the brain. They found that colonizing an adult germ-free animal with normal gut bacteria had no effect on their behavior. However, if germ free animals were colonized early in life, these effects could be reversed. This suggests that there is a critical period in the development of the brain when the bacteria are influential.

Consistent with these behavioral findings, two genes implicated in anxiety -- nerve growth factor-inducible clone A (NGF1-A) and brain-derived neurotrophic factor (BDNF) -- were found to be down-regulated in multiple brain regions in the germ-free animals. These changes in behavior were also accompanied by changes in the levels of several neurotransmitters, chemicals which are responsible for signal transmission between nerve cells. The neurotransmitters dopamine, serotonin and noradrenaline were elevated in a specific region of the brain, the striatum, which is associated with the planning and coordination of movement and which is activated by novel stimuli, while there were there were no such effects on neurotransmitters in other brain regions, such as those involved in memory (the hippocampus) or executive function (the frontal cortex).

When Pettersson’s team performed a comprehensive gene expression analysis of five different brain regions, they found nearly 40 genes that were affected by the presence of gut bacteria. Not only were these primitive microbes able to influence signaling between nerve cells while sequestered far away in the gut, they had the astonishing ability to influence whether brain cells turn on or off specific genes.

How, then, do these single-celled intestinal denizens exert their influence on a complex multicellular organ such as the brain? Although the answer is unclear, there are several possibilities: the Vagus nerve, for example, connects the gut to the brain, and it’s known that infection with the Salmonella bacteria stimulates the expression of certain genes in the brain, which is blocked when the Vagus nerve is severed. This nerve may be stimulated as well by normal gut microbes, and serve as the link between them and the brain. Alternatively, those microbes may modulate the release of chemical signals by the gut into the bloodstream which ultimately reach the brain. These gut microbes, for example, are known to modulate stress hormones which may in turn influence the expression of genes in the brain.

Regardless of how these intestinal “guests” exert their influence, these studies suggest that brain-directed behaviors, which influence the manner in which animals interact with the external world, may be deeply influenced by that animal’s relationship with the microbial organisms living in its gut. And the discovery that gut bacteria exert their influence on the brain within a discrete developmental stage may have important implications for developmental brain disorders.

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ABOUT THE AUTHOR(S)

Robert Martone is the Neuroscience therapeutic area lead for The Covance Biomarker Center of Excellence located in Greenfield, Indiana. He is a research scientist with extensive experience in drug discovery for neurodegenerative diseases.

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